Anti-HIV composition containing imidazole derivative

ABSTRACT

An anti-HIV composition comprising 2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazole or the pharmaceutical acceptable salt thereof and other one or more anti-HIV compounds is provided.

TECHNICAL FIELD

The present invention relates to pharmaceutical compositions comprisingtwo or more anti-HIV compounds.

BACKGROUND ART

AIDS (Acquired immunodeficiency syndrome) has been sweeping worldwide asan intractable disease caused by HIV (human immunodeficiency virus). Theresearch and development of the therapeutic agents are also performedglobally, however, have not given satisfaction yet. At present, anti-HIVcompositions which have been used or tested clinically are exemplifiedby nucleoside derivatives such as azidodeoxythymidine (AZT),dideoxyinosine (ddI), dideoxycytidine (ddC), dideoxydidehydrothymidine(d4T), 3'-thiacytidine (3TC), and the like as main therapeutic agents.

But all of these agents have serious side effects such as pancreatitis,anemia, leukopenia, neutropenia, emesis, aphagia, gastric disorder,anthema, insomnia, illusion, myospasm, dyspnea, dysuria, renalinsufficiency, hypacusis, and the like. The agents have many problemssuch as the emergence of drug resistant viruses by the prolongedadministration and followed by reduction of efficacy of agents, and thelike.

In order to reduce these problems, at present, the treatment withmultiple anti-HIV compositions have been generally adopted.

Under these situations, it has been reported that administration ofmultiple anti-HIV compounds show synergy. The examples of the synergyare combination of 3TC with non-nucleoside anti-HIV compounds such as{[(benzoxazol-2-yl)methyl]amino}-5-alkyl-6-alkyl-2-(1H)-pyridinone andthe like disclosed in JP-A 7-508997, and similar combination of 3TC with11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,3-b;21,31-e][1,4]diazepin-6-onedisclosed in JP-A 7-508998.

Problems such as serious side effects of anti-HIV compounds, theemergency of resistant viruses, and the like are pointed out. Newcombination of anti-HIV compounds which show synergy, that is,compositions comprising the compounds as an active ingredient have beendesired.

DISCLOSURE OF INVENTION

The present inventors found that administration of2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-iropropyl-1-(pyridin-4-yl)methyl-1H-imidazole (referred to as a CDIMI hereinafter) or thepharmaceutical acceptable salt thereof in combination with other one ormore anti-HIV compounds gives synergy by raising anti-HIV activity ofeach other.

Accordingly, one of the objects of the present invention is to providean anti-HIV composition comprising CDIMI or the pharmaceuticalacceptable salt thereof and other one or more anti-HIV compounds. Thepresent invention also provides a method for treating or preventing ofAIDS which comprises administering CDIMI or the pharmaceuticalacceptable salt thereof simultaneously or continuously with other one ormore anti-HIV compounds.

Another object of the present invention is to provide a use of CDIMI orthe pharmaceutical acceptable salt thereof and anti-HIV compounds, forthe manufacture of a medicament for treating or preventing of AIDS. Thepresent invention further relates to a method for inhibiting propagationof HIV by contacting HIV virus to CDIMI or the pharmaceutical acceptablesalt thereof in combination with other one or more anti-HIV compounds.The present invention relates to combination of CDIMI or thepharmaceutical acceptable salt thereof with other one ore more anti-HIVcompounds.

CDIMI of the present invention is described in WO 96/10019 and thesynthesis and the anti-HIV activity of the compound have been disclosedin the specification.

BRIEF DESCRIPTION OF DRAWING

FIG. 1 shows correlation a concentration of an anti-HIV compound and atoxicity (CC₅₀) CEM cells.

FIG. 2 shows correlation between a concentration of an anti-HIV compoundand a toxicity (CC₅₀) to U937 cells.

FIG. 3 shows correlation between a concentration of an anti-HIV compoundand a growth inhibition (IC₅₀) to CEM cells.

FIG. 4 shows correlation between a concentration of an anti-HIV compoundand a growth inhibition (IC₅₀) to U937 cells.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present specification, pharmaceutical acceptable salts of CDIMIinclude, for example, salts with inorganic acids such as hydrochloricacid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid,hydrobromic acid, and the like, salts with organic acids such as formicacid, acetic acid, tartaric acid, lactic acid, citric acid, fumaricacid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonicacid, camphorsulfonic acid, and the like, and salts with alkali metalsor alkali earth metals such as sodium, potassium, calcium, and the like.

The term "anti-HIV compound" of the present invention means anycompounds having anti-HIV activity without particular limitation, forexample, anti-virus compounds having anti-HIV activity such as anucleoside reverse transcriptase inhibitor, a non-nucleoside reversetranscriptase inhibitor, an HIV protease inhibitor, a DNA polymeraseinhibitor, and the like.

In the embodiment, a nucleoside reverse transcriptase inhibitor includesAZT, ddI, ddC, d4T, 3TC, and the like, a non-nucleoside reversetranscriptase inhibitor includes the compounds described in WO 96/10019,for example,3-(5-(3,5-dichlophenylthio)-4-isopropyl-1-(pyridin-4-ylmethyl)-1H-imidazol-2-ylpropan-1-olor 2-[5-(3,5-dichlorophenylthio)-1-ethyl-4-isopropyl-1H-imidazol-2-yl]ethanol, and the like, an HIV protease inhibitorincludes saquinavir, indinavir, ritonavir, nelfinavir, VX-478, and thelike. The other medicaments having anti-HIV activity include, forexample, foscarnet, a therapeutic agent of cytomegalovirus retinitishaving DNA polymerase inhibition activity and reverse transcriptaseinhibition activity, and the like. Particularly, AZT, ddI, ddC, 3TC,saquinavir, or foscarnet is preferred because of a high synergy ofanti-HIV activity in combination with CDIMI. More particularly, AZT,ddI, ddC, saquinavir, or foscarnet is preferred, the most particularly,AZT, ddC or saquinavir is preferred. AZT and ddC which significantlyinhibit the emergency of drug resistant viruses are most preferred.

An anti-HIV composition of the present invention can provide aneffective treatment for AIDS because it shows synergy as compared to theadministration of each anti-HIV compound and the like as a single agent.Specifically, because an anti-HIV composition of the present inventionshows synergy of anti-HIV activity as shown in the following experiment,a less administration dose than that for a single agent of each anti-HIVcompound gives enough anti-HIV activity, resulting in the reduction ofside effects such as toxicity, and the like. Administration of thecomposition of the present invention which contains an equal amount ofeach anti-HIV compound to a dose for its single agent effectivelyinhibits the emergency of drug resistant viruses and obviously bringsabout potent and effective treatment.

Accordingly, an anti-HIV composition of the present invention is aneffective pharmaceutical composition as a medicament for treating orpreventing of AIDS.

The present invention is characterized by synergistic effect of CDIMI incombination with other one or more anti-HIV compounds. Accordingly, eachactive ingredient may be administered simultaneously as a composition.Continuous administration of each active ingredient at intervals of timethat synergy is maintained gives the same effect.

When administering an anti-HIV composition of the present invention, itcan safely be administered orally or parenterally. For oraladministration, it may be administered as conventional formulations suchas tablets, granules, powder, capsules, pilulae, liquid solutions,syrup, buccals, sublingual tablets, and the like. For parenteraladministration, it can preferably be administered into any formulations,for example, injections such as intramuscular injection and the like,suppository, endermism, inhalations, and the like, in particular, oraladministration is preferred.

The pharmaceutical composition of the present invention can be preparedby mixing an effective amount of active ingredients, if necessary, withmedicinal additives suitable for a final administration formulation suchas carriers, binders, wetting agents, disintegrating agents, lubricants,diluents, and the like. For example, injections may be prepared bysterilization with suitable carriers.

In the embodiment, carriers include lactose, sucrose, glucose, starch,calcium carbonate, crystalline cellulose, and the like, binders includemethylcellulose, carboxymethylcellulose, hydroxypropylcellulose,gelatin, polyvinylpyrolidone, and the like, disintegrating agentsinclude carboxymethylcellulose, sodium carboxymethylcellulose, starch,sodium alginate, powdered agar, sodium lauryl sulfate, and the like, andlubricants include talc, magnesium stearate, macrogol, and the like.Bases of suppositories include cocoa butter, macrogol, methylcellulose,and the like. In preparing liquid preparations or emulsion or suspensioninjection, conventional solubilizing agents, emulsifiers, stabilizingagents, preservatives, isotonizing agents, and the like may be added,and additionally. For oral administration, sweetening agents, flavoringagents, and the like may be added.

As an active ingredient of an anti-HIV composition of the presentinvention, CDIMI may be combined with one or more of other anti-HIVcompounds.

In the case of administering CDIMI or other anti-HIV active compounds asa single agent, the administration dose for each active ingredient isusually 0.05 mg-3000 mg/day, preferably 0.1 mg-1000 mg/day, parenterally0.01 mg-1000 mg/day, preferably 0.05 mg-500 mg/day.

In the case of administering an anti-HIV composition of the presentinvention, the dose of each active ingredient in the formulation shouldbe determined in consideration of the patients' age and body-weight, thecondition of diseases, the administration route, and the like. However,the amount of each active ingredient in the composition may be 0.1-1times as the above administration dose of the each anti-HIV compound asa single agent. Accordingly, in the case of administering CDIMI andother anti-HIV compounds together as an anti-HIV composition of thepresent invention, the dose of each active ingredient may be 0.005mg-3000 mg/day, preferably 0.01 mg-1000 mg/day for oral administration,0.001 mg-1000 mg/day, preferably 0.005 mg-500 mg/day for parenteraladministration. It can be administered in one to several times divisionsper day.

EXAMPLE

Examples and Experiments of the present invention are provided tofurther illustrate in detail the present invention and are not to beconstrued as limiting the scope.

Experiment 1

Synergy of Anti-HIV Activity

Human T cell line Molt-4 cells persistently infected with HIV-1 (IIIBstrain clone 2) were cultured in RPMI-1640 medium supplemented with 10%fetal calf serum, and the supernatant was filtered and stored at -80° C.after the virus titer was determined.

Two-fold dilution of CDIMI concentration from 10 ng/ml to 0.157 ng/mland 0 ng/ml, and two-fold dilution of AZT concentration from 100 ng/mlto 0.4 ng/ml and 0 ng/ml were prepared. The combination of these twodrugs was conducted by the checker board method using 96-wellmicroplates. Fifty μl of the above medium containing 10⁵ cells/ml ofMT-4 was added to each well of 96-well microplates, and 50 μl of AZTtwo-fold diluted by the same medium was added to each well. After 4hours, 50 μl of the culture supernatant of the above HIV-1 IIIB strainclone 2 was added, at the same time 50 μl of CDIMI in two-fold dilutionwas also added, followed by incubation in 5% CO₂ incubator at 37° C. for5 days.

Virus titers in the culture supernatant were calculated by taking viralreverse transcriptase activity as an index determined by the followingmethod:

To 100 μl of a reaction mixture containing 50 mM Tris-HCl, pH 8.3, 150mM KCl, 10 mM MgCl₂, 0.1% Nonidet P-40, 10 mM dithiothreitol, 5 μg/lpoly(A), 5 μg/ml (dT)₁₂₋₁₈, and 1 μCi [³ H]dTTP was added 10 μl of theculture supernatant, and incubated at 37° C. for 3 hours. The reactionmixture was chilled on ice and transferred by a cell harvester to aDEAE-Filtermat. The filter was washed with 5% Na₂ HPO₄.12H₂ O and H₂ O,and the radioactivity incorporated in DNA was measured by an LKB BetaPlate scintillation counter to determine viral reverse transcriptaseactivity.

Three assays were conducted and the mean value of reverse transcriptaseinhibition rate (%) was calculated by being compared to the enzymaticactivity in the absence of CDIMI and AZT. The result is shown in Table1.

                                      TABLE 1                                     __________________________________________________________________________               A Z T (ng/ml)                                                                 0   0.4                                                                              0.8                                                                              1.6                                                                              3.13                                                                             6.25                                                                             12.5                                                                             25 50 100                                    __________________________________________________________________________    CDIMI (ng/ml)                                                                        10  99.72                                                                             99.69                                                                            99.69                                                                            99.7                                                                             99.69                                                                            99.7                                                                             99.66                                                                            99.67                                                                            99.62                                                                            99.64                                         5   99.63                                                                             99.67                                                                            99.65                                                                            99.61                                                                            99.63                                                                            99.61                                                                            99.62                                                                            99.64                                                                            99.63                                                                            99.63                                         2.5 99.62                                                                             99.64                                                                            99.61                                                                            99.62                                                                            99.64                                                                            99.61                                                                            99.64                                                                            99.63                                                                            99.63                                                                            99.65                                         1.25                                                                              99.07                                                                             99.57                                                                            99.6                                                                             99.6                                                                             99.56                                                                            99.59                                                                            99.62                                                                            99.64                                                                            99.61                                                                            99.65                                         0.625                                                                             77.94                                                                             99.33                                                                            99.55                                                                            99.6                                                                             99.55                                                                            99.6                                                                             99.62                                                                            99.63                                                                            99.63                                                                            99.65                                         0.313                                                                             3.02                                                                              96.72                                                                            98.33                                                                            99.44                                                                            99.4                                                                             99.54                                                                            99.61                                                                            99.65                                                                            99.67                                                                            99.68                                         0.157                                                                             -14.4                                                                             79.15                                                                            92.19                                                                            98.89                                                                            99.03                                                                            99.44                                                                            99.41                                                                            99.63                                                                            99.68                                                                            99.67                                         0   0   -7.82                                                                            43.43                                                                            77 96.3                                                                             98.6                                                                             99.33                                                                            99.56                                                                            99.64                                                                            99.66                                  __________________________________________________________________________

On the assumption that the inhibition of the two anti-HIV compounds wasadditive, virus growth inhibition rate was calculated on allcombinations of concentrations according to the formula (I)

    Z=X+Y(1-X)                                                 (I)

wherein Z means an additive inhibition rate, X is an inhibition rate ofCDIMI and Y is an inhibition rate of the other anti-HIV compound. Forexample, when CDIMI was 5 ng/ml and AZT was 0.8 ng/ml, X is 99.63% whenCDIMI is 5 ng/ml and AZT is 0 ng/ml in Table 1, and Y is 43.43% whenCDIMI is 0 ng/ml and AZT is 0.8 ng/ml in Table 1. Then the additiveinhibition rate Z is calculated to be 99.79% according to the formula(I).

Next, a difference between the measured values in Table 1 and acalculated additive inhibition rate as the above was calculated. Theresult is shown in Table 2, and the 99% confidential limit value isshown in Table 3.

                                      TABLE 2                                     __________________________________________________________________________               A Z T (ng/ml)                                                                 0 0.4 0.8                                                                              1.57                                                                             3.13                                                                             6.25                                                                             12.5                                                                             25 50 100                                     __________________________________________________________________________    CDIMI (ng/ml)                                                                        10  0 -0.01                                                                             -0.15                                                                            -0.24                                                                            -0.3                                                                             -0.3                                                                             -0.34                                                                            -0.33                                                                            -0.38                                                                            -0.36                                          5   0 0.07                                                                              -0.14                                                                            -0.3                                                                             -0.36                                                                            -0.38                                                                            -0.38                                                                            -0.36                                                                            -0.37                                                                            -0.37                                          2.5 0 0.05                                                                              -0.18                                                                            -0.29                                                                            -0.35                                                                            -0.38                                                                            -0.36                                                                            -0.37                                                                            -0.37                                                                            -0.35                                          1.25                                                                              0 0.57                                                                              0.13                                                                             -0.19                                                                            -0.41                                                                            -0.4                                                                             -0.37                                                                            -0.36                                                                            -0.39                                                                            -0.35                                          0.625                                                                             0 23.12                                                                             12.03                                                                            4.67                                                                             0.37                                                                             -0.09                                                                            -0.23                                                                            -0.27                                                                            -0.29                                                                            0.27                                           0.312                                                                             0 101.28                                                                            53.19                                                                            21.75                                                                            2.99                                                                             0.9                                                                              0.26                                                                             0.08                                                                             0.02                                                                             0.01                                           0.157                                                                             0 102.5                                                                             56.91                                                                            25.2                                                                             3.26                                                                             1.04                                                                             0.18                                                                             0.13                                                                             0.09                                                                             0.06                                           0   0 0   0  0  0  0  0  0  0  0                                       __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________               A Z T (ng/ml)                                                                 0 0.4  0.8 1.57                                                                              3.13                                                                              6.25                                                                              12.5                                                                              25  50  100                             __________________________________________________________________________    CDIMI (ng/ml)                                                                        10  0 0    -0.099                                                                            -0.214                                                                            -0.274                                                                            -0.249                                                                            -0.289                                                                            -0.304                                                                            -0.329                                                                            -0.36                                  5   0 0.0443                                                                             -0.089                                                                            -0.274                                                                            -0.334                                                                            -0.303                                                                            -0.354                                                                            -0.283                                                                            -0.293                                                                            -0.293                                 2.5 0 0.0243                                                                             -0.129                                                                            -0.213                                                                            -0.247                                                                            -0.303                                                                            -0.283                                                                            -0.242                                                                            -0.319                                                                            -0.273                                 1.25                                                                              0 0.5186                                                                             0.0529                                                                            -0.139                                                                            -0.281                                                                            -0.349                                                                            -0.319                                                                            -0.309                                                                            -0.313                                                                            -0.299                                 0.625                                                                             0 23.069                                                                             11.927                                                                            4.5929                                                                            0.2672                                                                            -0.013                                                                            -0.179                                                                            -0.167                                                                            -0.213                                                                            -0.219                                 0.312                                                                             0 100.61                                                                             52.65                                                                             21.699                                                                            2.7587                                                                            0.8229                                                                            0.2343                                                                            0.0286                                                                            0   0                                      0.157                                                                             0 101.91                                                                             54.417                                                                            24.917                                                                            3.1572                                                                            0.8858                                                                            0.0515                                                                            0.0786                                                                            0.0386                                                                            0.0086                                 0   0 0    0   0   0   0   0   0   0   0                               __________________________________________________________________________

When the measured value is greater than the additive inhibition rate,namely, the value is more than 0 in Table 3, it is judged as havingsynergy. Synergy volume is designated as total sum of values more than 0in Table 3.

According to the same method, data analysis was conducted on theexperiment results using ddI, ddC, saquinavir, and foscarnet instead ofAZT.

Addition to cells of saquinavir and foscarnet was done at the same timeas that of CDIMI when the virus was infected. For the combination withddC, ddI and saquinavir, the CDIMI concentration was ranged from 5 ng/mlto 0.08 ng/ml in two-fold dilution and 0 ng/ml, and the concentrationsof ddC, ddI, saquinavir, and foscarnet were ranged from 500 ng/ml to 2ng/ml in two-fold dilution and 0 ng/ml.

The result of the analysis is shown below. Tables 4-6 show the resultsof ddI, Tables 7-9 show the results of ddC, Tables 10-12 show theresults of saquinavir, and Tables 13-15 show the results of foscarnet.

                                      TABLE 4                                     __________________________________________________________________________               d d I (ng/ml)                                                                 0  2  4  8  16 31.25                                                                            62.5                                                                             125                                                                              250                                                                              500                                     __________________________________________________________________________    CDIMI (ng/ml)                                                                        5   99.01                                                                            99.05                                                                            99 99.11                                                                            99.13                                                                            99.16                                                                            99.17                                                                            99.08                                                                            99.1                                                                             99.15                                          2.5 99.13                                                                            99.02                                                                            99.01                                                                            98.98                                                                            99.12                                                                            99.05                                                                            99.06                                                                            98.98                                                                            98.96                                                                            98.91                                          1.25                                                                              99.01                                                                            98.93                                                                            98.99                                                                            98.91                                                                            98.97                                                                            98.98                                                                            99.07                                                                            99.01                                                                            98.96                                                                            98.94                                          0.625                                                                             98.83                                                                            98.7                                                                             98.74                                                                            98.91                                                                            98.93                                                                            98.96                                                                            98.91                                                                            98.92                                                                            98.84                                                                            98.87                                          0.313                                                                             98.71                                                                            98.73                                                                            98.72                                                                            98.91                                                                            98.76                                                                            98.78                                                                            98.69                                                                            98.73                                                                            98.65                                                                            98.84                                          0.16                                                                              95.65                                                                            96.68                                                                            97.41                                                                            97.55                                                                            97.44                                                                            97.51                                                                            97.66                                                                            97.94                                                                            97.64                                                                            98.3                                           0.08                                                                              29.23                                                                            47.08                                                                            71.08                                                                            78.19                                                                            60.86                                                                            70.83                                                                            62.05                                                                            79.74                                                                            80.45                                                                            91.19                                          0   0  12.52                                                                            15.2                                                                             5.83                                                                             26.23                                                                            20.43                                                                            31.66                                                                            30.86                                                                            40.65                                                                            50.13                                   __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________               d d I (ng/ml)                                                                 0 2  4  8  16 31.25                                                                            62.5                                                                             125                                                                              250                                                                              500                                      __________________________________________________________________________    CDIMI (ng/ml)                                                                        5   0 -0.08                                                                            -0.16                                                                            0.04                                                                             -0.14                                                                            -0.05                                                                            -0.15                                                                            -0.24                                                                            -0.31                                                                            -0.36                                           2.5 0 -0.22                                                                            -0.25                                                                            -0.2                                                                             -0.24                                                                            -0.26                                                                            -0.35                                                                            -0.42                                                                            -0.52                                                                            -0.66                                           1.25                                                                              0 -0.2                                                                             -0.17                                                                            -0.16                                                                            -0.3                                                                             -0.23                                                                            -0.25                                                                            -0.31                                                                            -0.45                                                                            -0.57                                           0.625                                                                             0 -0.28                                                                            -0.27                                                                            0.01                                                                             -0.21                                                                            -0.11                                                                            -0.29                                                                            -0.27                                                                            -0.47                                                                            -0.55                                           0.313                                                                             0 -0.14                                                                            -0.19                                                                            0.02                                                                             -0.29                                                                            -0.19                                                                            -0.43                                                                            -0.38                                                                            -0.58                                                                            -0.52                                           0.16                                                                              0 0.49                                                                             1.1                                                                              1.65                                                                             0.65                                                                             0.97                                                                             0.63                                                                             0.95                                                                             0.22                                                                             0.47                                            0.08                                                                              0 8.99                                                                             31.09                                                                            44.83                                                                            13.07                                                                            27.14                                                                            10.41                                                                            28.67                                                                            22.45                                                                            26.48                                           0   0 0  0  0  0  0  0  0  0  0                                        __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________               d d I (ng/ml)                                                                 0 2   4   8   16  31.25                                                                             62.5                                                                              125 250 500                              __________________________________________________________________________    CDIMI (ng/ml)                                                                        5   0 0   -0.109                                                                            0   -0.11                                                                             0   0   -0.163                                                                            -0.027                                                                            -0.206                                  2.5 0 0   0   0   -0.009                                                                            -0.234                                                                            -0.247                                                                            -0.24                                                                             -0.314                                                                            -0.583                                  1.25                                                                              0 -0.071                                                                            0   -0.006                                                                            0   -0.101                                                                            0   -0.13                                                                             -0.373                                                                            -0.185                                  0.625                                                                             0 0   -0.064                                                                            0   0   0   0   -0.219                                                                            -0.033                                                                            -0.216                                  0.313                                                                             0 0   -0.139                                                                            0   -0.007                                                                            -0.061                                                                            0   -0.02                                                                             -0.066                                                                            -0.314                                  0.16                                                                              0 0.2844                                                                            0.9715                                                                            0.4164                                                                            0.4701                                                                            0.5331                                                                            0.1417                                                                            0.7958                                                                            0   0                                       0.08                                                                              0 3.7472                                                                            27.209                                                                            40.615                                                                            6.1053                                                                            18.505                                                                            0   22.631                                                                            17.284                                                                            23.499                                  0   0 0   0   0   0   0   0   0   0   0                                __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________               d d C (ng/ml)                                                                 0  2  4  8  16 31.25                                                                            62.5                                                                             125                                                                              250                                                                              500                                     __________________________________________________________________________    CDIMI (ng/ml)                                                                        5   99.1                                                                             99.04                                                                            99.17                                                                            99.06                                                                            99.3                                                                             99.15                                                                            99.16                                                                            99.14                                                                            99.08                                                                            99.12                                          2.5 98.97                                                                            99 98.95                                                                            98.93                                                                            99.04                                                                            99.02                                                                            99.09                                                                            99.05                                                                            98.92                                                                            98.87                                          1.25                                                                              98.88                                                                            98.96                                                                            98.96                                                                            98.99                                                                            98.93                                                                            98.9                                                                             99.03                                                                            98.88                                                                            98.86                                                                            98.96                                          0.625                                                                             98.82                                                                            98.81                                                                            98.81                                                                            98.88                                                                            98.78                                                                            98.91                                                                            98.87                                                                            98.76                                                                            98.79                                                                            98.85                                          0.313                                                                             98.61                                                                            98.68                                                                            98.66                                                                            98.68                                                                            98.87                                                                            98.88                                                                            98.66                                                                            98.76                                                                            98.65                                                                            98.84                                          0.16                                                                              95.41                                                                            96.36                                                                            97.41                                                                            97.94                                                                            97.91                                                                            96.57                                                                            98.7                                                                             98.7                                                                             98.7                                                                             98.67                                          0.08                                                                              1.88                                                                             69.08                                                                            72.58                                                                            89.42                                                                            90.05                                                                            97.36                                                                            98.29                                                                            98.59                                                                            98.61                                                                            98.68                                          0   0  6.21                                                                             14.36                                                                            14.92                                                                            18.61                                                                            42.96                                                                            62.66                                                                            83.25                                                                            98.23                                                                            98.66                                   __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________               d d C (ng/ml)                                                                 0 2  4  8  16 31.25                                                                            62.5                                                                             125                                                                              250                                                                              500                                      __________________________________________________________________________    CDIMI (ng/ml)                                                                        5   0 -0.12                                                                            -0.06                                                                            -0.17                                                                            0.03                                                                             -0.34                                                                            -0.5                                                                             -0.71                                                                            -0.9                                                                             -0.87                                           2.5 0 -0.03                                                                            -0.17                                                                            -0.19                                                                            -0.12                                                                            -0.39                                                                            -0.53                                                                            -0.78                                                                            -1.06                                                                            -1.12                                           1.25                                                                              0 0.01                                                                             -0.08                                                                            -0.06                                                                            -0.16                                                                            -0.46                                                                            -0.55                                                                            -0.93                                                                            -1.12                                                                            -1.02                                           0.625                                                                             0 -0.08                                                                            -0.18                                                                            -0.12                                                                            -0.26                                                                            -0.42                                                                            -0.69                                                                            -1.04                                                                            -1.19                                                                            -1.13                                           0.313                                                                             0 -0.02                                                                            -0.15                                                                            -0.14                                                                            0  -0.33                                                                            -0.82                                                                            -1.01                                                                            -1.33                                                                            -1.14                                           0.16                                                                              0 0.66                                                                             1.34                                                                             1.85                                                                             1.65                                                                             1.19                                                                             0.41                                                                             -0.53                                                                            -1.22                                                                            -1.27                                           0.08                                                                              0 61.11                                                                            56.61                                                                            72.9                                                                             69.91                                                                            53.33                                                                            34.93                                                                            15.03                                                                            0.35                                                                             -0.01                                           0   0 0  0  0  0  0  0  0  0  0                                        __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________               d d C (ng/ml)                                                                 0 2   4   8   16  37.25                                                                             62.5                                                                              125 250 500                              __________________________________________________________________________    CDIMI (ng/ml)                                                                        5   0 0   0   -0.041                                                                            0   -0.006                                                                            -0.269                                                                            -0.607                                                                            -0.823                                                                            -0.664                                  2.5 0 0   -0.119                                                                            0   0   -0.133                                                                            -0.479                                                                            -0.369                                                                            -0.906                                                                            -0.786                                  1.25                                                                              0 0   0   0   0   -0.383                                                                            -0.165                                                                            -0.802                                                                            -0.452                                                                            -0.892                                  0.25                                                                              0.                                                                              0   -0.026                                                                            -0.069                                                                            0   -0.112                                                                            -0.613                                                                            -0.809                                                                            -0.727                                                                            -1.079                                  0.313                                                                             0 0   0   0   0   0   -0.023                                                                            -0.702                                                                            -0.996                                                                            -0.832                                  0.16                                                                              0 0.403                                                                             0   1.7472                                                                            1.5729                                                                            0.933                                                                             0   -0.273                                                                            -1.143                                                                            -1.244                                  0.08                                                                              0 47.618                                                                            44.582                                                                            72.566                                                                            68.856                                                                            53.253                                                                            34.493                                                                            14.85                                                                             0.0673                                                                            0                                       0   0 0   0   0   0   0   0   0   0   0                                __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________               saquinavir (ng/ml)                                                            0  2  4  8  16 31.25                                                                            62.5                                                                             125                                                                              250                                                                              500                                     __________________________________________________________________________    CDIMI (ng/ml)                                                                        5   99.25                                                                            99.21                                                                            99.2                                                                             99.2                                                                             99.1                                                                             99.12                                                                            99.17                                                                            99.04                                                                            99.06                                                                            99.05                                          2.5 99.14                                                                            99.01                                                                            99.06                                                                            99.07                                                                            98.98                                                                            98.93                                                                            99.2                                                                             98.8                                                                             98.88                                                                            98.95                                          1.25                                                                              99.04                                                                            98.85                                                                            98.73                                                                            98.91                                                                            98.76                                                                            98.58                                                                            98.91                                                                            98.85                                                                            98.72                                                                            98.79                                          0.625                                                                             98.77                                                                            98.78                                                                            98.6                                                                             98.61                                                                            98.71                                                                            98.7                                                                             98.63                                                                            98.63                                                                            98.55                                                                            98.71                                          0.313                                                                             98.71                                                                            98.37                                                                            98.56                                                                            98.67                                                                            98.8                                                                             98.72                                                                            98.58                                                                            98.69                                                                            98.54                                                                            98.56                                          0.16                                                                              96.94                                                                            98.01                                                                            98.2                                                                             98.54                                                                            98.59                                                                            98.6                                                                             98.85                                                                            98.75                                                                            98.41                                                                            98.41                                          0.08                                                                              -1.13                                                                            91.93                                                                            97.16                                                                            97.77                                                                            97.62                                                                            98.54                                                                            98.49                                                                            98.43                                                                            98.44                                                                            98.45                                          0   0  0.91                                                                             -2.49                                                                            21.48                                                                            72 86.33                                                                            91.51                                                                            93.49                                                                            94.2                                                                             93.95                                   __________________________________________________________________________

                                      TABLE 11                                    __________________________________________________________________________           saquinavir (ng/ml)                                                            0 2  4   8  16 31.25                                                                            62.5                                                                             125                                                                              250                                                                              500                                         __________________________________________________________________________    CDIMI (ng/ml)                                                                 5      0 -0.05                                                                            -0.03                                                                             -0.21                                                                            -0.69                                                                            -0.78                                                                            -0.77                                                                            -0.91                                                                            -0.9                                                                             -0.9                                        2.5    0 -0.14                                                                            -0.06                                                                             -0.25                                                                            -0.78                                                                            -0.95                                                                            -0.73                                                                            -1.14                                                                            -1.07                                                                            -1                                          1.25   0 -0.2                                                                             -0.29                                                                             -0.34                                                                            -0.97                                                                            -1.29                                                                            -1.01                                                                            -1.09                                                                            -1.22                                                                            -1.15                                       0.625  0 0  -0.14                                                                             -0.42                                                                            -0.95                                                                            -1.13                                                                            -1.27                                                                            -1.29                                                                            -1.38                                                                            -1.22                                       0.313  0 -0.35                                                                            -0.12                                                                             0.32                                                                             -0.84                                                                            -1.1                                                                             -1.31                                                                            -1.23                                                                            -1.39                                                                            -1.36                                       0.16   0 1.04                                                                             1.34                                                                              0.94                                                                             -0.55                                                                            -0.98                                                                            -0.89                                                                            -1.05                                                                            -1.41                                                                            -1.4                                        0.08   0 92.14                                                                            100.81                                                                            77.18                                                                            25.94                                                                            12.36                                                                            7.08                                                                             5.01                                                                             4.31                                                                             4.57                                        0      0 0  0   0  0  0  0  0  0  0                                           __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________           saquinavir (ng/ml)                                                            0 2   4   8   16  31.25                                                                             62.5                                                                              125 250 500                                  __________________________________________________________________________    CDIMI (ng/ml)                                                                 5      0 0   0   0   -0.484                                                                            -0.574                                                                            -0.641                                                                            -0.833                                                                            -0.592                                                                            -0.515                               2.5    0 0   0   -0.019                                                                            -0.549                                                                            -0.693                                                                            -0.447                                                                            -0.78                                                                             -0.942                                                                            -0.769                               1.25   0 -0.02                                                                             -0.059                                                                            0   -0.739                                                                            -1.084                                                                            -0.599                                                                            -0.807                                                                            -1.066                                                                            -0.996                               0.625  0 0   0   0   -0.822                                                                            -0.899                                                                            -0.833                                                                            -0.802                                                                            -1.174                                                                            -1.117                               0.313  0 0   0   -0.063                                                                            -0.66                                                                             -0.689                                                                            -0.925                                                                            -0.87                                                                             -1.056                                                                            -0.975                               0.16   0 0.3461                                                                            0.3634                                                                            0.5031                                                                            -0.165                                                                            0   -0.376                                                                            -0.793                                                                            -1.307                                                                            -0.629                               0.08   0 83.531                                                                            97.957                                                                            76.049                                                                            25.349                                                                            10.664                                                                            6.566                                                                             4.5474                                                                            4.1815                                                                            4.1588                               0      0 0   0   0   0   0   0   0   0   0                                    __________________________________________________________________________

                                      TABLE 13                                    __________________________________________________________________________           foscarnet (ng/ml)                                                             0  2  4  8  16 31.25                                                                            62.5                                                                             125                                                                              250                                                                              500                                         __________________________________________________________________________    CDIMI (ng/ml)                                                                 10     98.62                                                                            98.78                                                                            98.73                                                                            98.51                                                                            98.56                                                                            98.71                                                                            98.49                                                                            98.5                                                                             98.62                                                                            98.52                                       5      98.33                                                                            98.96                                                                            98.99                                                                            99 99.02                                                                            98.77                                                                            98.74                                                                            98.66                                                                            98.73                                                                            98.85                                       2.5    97.99                                                                            98.62                                                                            98.8                                                                             99.15                                                                            98.26                                                                            98.44                                                                            98.8                                                                             98.39                                                                            98.6                                                                             98.64                                       1.25   91.78                                                                            92.23                                                                            92.96                                                                            92.48                                                                            92.63                                                                            95.15                                                                            95.13                                                                            96.36                                                                            97.68                                                                            98.52                                       0.625  34.93                                                                            47.31                                                                            61.09                                                                            72.46                                                                            75.1                                                                             84.61                                                                            91.03                                                                            92.57                                                                            96.28                                                                            96.98                                       0.313  33.97                                                                            39.29                                                                            47.9                                                                             53.56                                                                            63.68                                                                            72.23                                                                            87.93                                                                            90.56                                                                            93.45                                                                            96.91                                       0.157  19.14                                                                            21.57                                                                            30.44                                                                            20.42                                                                            36.34                                                                            41.02                                                                            34.76                                                                            83.9                                                                             88.94                                                                            89.91                                       0      0  15.84                                                                            11.05                                                                            25.35                                                                            33.03                                                                            32.6                                                                             40.2                                                                             54.76                                                                            75.76                                                                            83.89                                       __________________________________________________________________________

                                      TABLE 14                                    __________________________________________________________________________           foscarnet (ng/ml)                                                             0 2   4  8   16 31.25                                                                            62.5                                                                              125                                                                              250                                                                              500                                       __________________________________________________________________________    CDIMI (ng/ml)                                                                 10     0 -0.06                                                                             -0.04                                                                            -0.46                                                                             -0.52                                                                            -0.36                                                                            -0.68                                                                             -0.88                                                                            -1.05                                                                            -1.26                                     5      0 0.37                                                                              0.48                                                                             0.25                                                                              0.14                                                                             -0.1                                                                             -0.26                                                                             -0.58                                                                            -0.87                                                                            -0.88                                     2.5    0 0.31                                                                              0.59                                                                             0.65                                                                              -0.39                                                                            -0.21                                                                            0   -0.7                                                                             -0.91                                                                            -1.04                                     1.25   0 -0.85                                                                             0.27                                                                             -1.38                                                                             -1.87                                                                            0.69                                                                             0.05                                                                              0.08                                                                             -0.33                                                                            -0.16                                     0.625  0 2.07                                                                              18.97                                                                            21.03                                                                             18.68                                                                            28.47                                                                            29.94                                                                             22.01                                                                            12.05                                                                            7.46                                      0.313  0 -5.14                                                                             6.63                                                                             2.85                                                                              7.9                                                                              16.73                                                                            27.42                                                                             20.43                                                                            9.46                                                                             7.55                                      0.157  0 -10.38                                                                            2.36                                                                             -19.22                                                                            -9.51                                                                            -4.48                                                                            -16.89                                                                            20.48                                                                            8.54                                                                             2.94                                      0      0 0   0  0   0  0  0   0  0  0                                         __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________           foscarnet (ng/ml)                                                             0 2 4   8 16                                                                              31.25                                                                            62.5                                                                              125 250 500                                         __________________________________________________________________________    CDIMI (ng/ml)                                                                 10     0 0 0   0 0 0  0   0   0   -0.566                                      5      0 0 0.0945                                                                            0 0 0  0   0   0   0                                           2.5    0 0 0   0 0 0  0   0   0   -0.86                                       1.25   0 0 0   0 0 0  0   0   0   0                                           0.625  0 0 0   0 0 0  16.242                                                                            14.917                                                                            7.5525                                                                            2.9368                                      0.313  0 0 0   0 0 0  19.53                                                                             8.4024                                                                            0   4.9029                                      0.157  0 0 0   0 0 0  0   0.0742                                                                            1.1641                                                                            0                                           0      0 0 0   0 0 0  0   0   0   0                                           __________________________________________________________________________

All data analyses were conducted by Mac Synergy II soft (Prichard, M. N.and Shipman, C., Jr., Antiviral Res 14: 181-206, 1990). According to themanual, synergy volume was judged as follows; when synergy volume is25-50, the synergy is small but significant (+), when synergy volume is50-100, the synergy is significant (++), and when synergy volume is morethan 100, the synergy is very high (+++).

Synergy volume within 99% confidential limit and the results of judgmentare shown in Table 16.

                  TABLE 16                                                        ______________________________________                                        Anti-HIV compound                                                                             Synergy volume                                                                            Synergy                                           ______________________________________                                        CDIMI + AZT     405         +++                                               CDIMI + ddI     163         +++                                               CDIMI + ddC     341         +++                                               CDIMI +         314         +++                                               saquinavir                                                                    CDIMI +         76          ++                                                foscarnet                                                                     ______________________________________                                    

Table 16 shows very high synergy of CDIMI in the combination with otheranti-HIV compounds.

Experiment 2

Cytotoxicity and Cell Growth Inhibition

For a cytotoxicity test and a cell growth inhibition test, 96-well flatbottom microplates were used. CDIMI from 50 μg/ml to 0.78 μg/ml intwo-fold dilution and 0 μg/ml, and AZT from 200 μg/ml to 0.18 μg/ml intwo-fold dilution and 0 μg/ml were prepared and two drugs were combinedby the checker board method.

(Cytotoxicity test)

CEM cells or U937 cells were cultured in RPMI-1640 medium supplementedwith 10% fetal calf serum. The cells were added to each well of 96 wellflat bottom microplates at 1×10⁴ cells per well, and CDIMI and AZTdiluted in the same medium were added to each well according to theabove method. The plates were incubated in 5% CO₂ incubator at 37° C.for 3 days, and to all wells were added 5 mg/ml of MTT(3{4,5-dimethylthiazol-2-yl}-2,5-diphenyltetrazolium bromide) and 30 μlof PBS and incubated for 1 hour. During this incubation, surviving cellsreduced MTT to insoluble formazan. From all wells 150 μl of the culturesupernatant was taken out and then 150 μl of a solution (isopropanolcontaining 10% Triton X-100 and 0.4% HCl) was added. Formazan wassolubilized by shaking and OD₅₆₀ nm was measured using OD₆₉₀ nm asreference wavelength. Fifty % cytotoxic concentration (CC₅₀) wascalculated and plotted results are shown in FIG. 1 and FIG. 2. FIG. 1 isthe result using CEM cells and FIG. 2 is the result using U937 cells.

(Cell growth inhibition test)

CEM cells or U937 cells were cultured in RPMI-1640 medium supplementedwith 10% fetal calf serum. The cells were added to each well of 96 wellflat bottom microplates at 1×10⁴ cells per well, and CDIMI and AZTdiluted in the same medium were added to each well by the above method.The plates were incubated in 5% CO₂ incubator at 37° C. for 5 hours, andto each well was added 0.2 μCi [³ H] thymidine and incubated for 24hours. The cells were collected by a cell harvester on a DEAE filter.Radioactivity incorporated in the cells was measured by Beta Platescintillation counter to determine cell growth. Fifty % inhibitionconcentration of [³ H] thymidine uptake (IC₅₀) was calculated andplotted results are shown in FIGS. 3 and FIG. 4. FIG. 3 is the resultusing CEM cells and FIG. 4 is the result using U937 cells.

FIG. 1 to FIG. 4 show that combination of CDIMI with AZT does not havesynergy in both cytotoxity and cell growth inhibition.

Experiment 3

Suppression of the Emergence of Drug Resistant Variants

an T cell line Molt-4 cells persistently infected with HIV-1 (IIIBstrain clone 3) were cultured in RPMI-1640 medium supplemented with 10%fetal calf serum, the supernatant was filtered and stored at 80° C.,after the virus titer was determined.

One ml of the above medium containing 10⁶ cells of M 8166 was added toeach well of 12-well plates, and 100 μl of the above HIV-1 IIIB strainclone 3 was added, and incubated for 2 hours for virus infection. Cellswere washed with the above medium, and 4 ml of the medium containingCDIMI or other anti-HIV compounds alone or their combination was addedto each well and incubated in 5% CO₂ incubator at 37° C. CDIMI was addedat 1 ng/ml and ddC was added at 50 ng/ml respectively and the sameconcentrations of them were added for the combination. Cells weresubcultured twice a week, and when viral growth was observed, the drugconcentration of the anti-HIV compound was doubled. In the case that noviral growth was observed, the drug concentration was kept the same asthat of the last culture.

Virus titer was determined using viral reverse transcriptase activity asa marker by the following method.

To 100 μl of the reaction mixture containing 50 mM Tris-HCl, pH 8.3, 150mM KCl, 10 mM MgCl₂, 0.1% Nonidet P-40, 10 mM dithiothreitol, 5 μg/mlpoly(A), 5 μg/ml (dT) ₁₂₋₁₈, and 1 μCi [³ H] dTTP was added 10 μl of theculture supernatant, and incubated at 37° C. for 3 hours. The reactionmixture was chilled on ice and collected by a cell harvester on aDEAE-Filtermat. The filter was washed with 5% Na₂ HP0₄.12H₂ O and H₂ O,and the radioactivity incorporated in DNA was measured by an LKB BetaPlate scintillation counter to determine viral reverse transcriptaseactivity.

When virus growth was observed, viruses were isolated and thesensitivity to each active ingredient was assayed by the usual method.The result is shown in Table 17.

                  TABLE 17                                                        ______________________________________                                                                  Ratio of resistance                                              Week of emergence                                                                          compared to parent                                  Anti-HIV compound                                                                          of resistant mutants                                                                       strain                                              ______________________________________                                        CDIMI        4 weeks      10 times                                            ddC          1 week       20 times                                            CDIMI +      >5 weeks     --                                                  ddC                                                                           ______________________________________                                    

Table 17 shows that a resistant variant did not appear in thecombination of ddC and CDIMI.

Experiment 4

Revision to Drug Sentitive Virus by the Combination of Drug ResistantMutations

By in vitro mutagenesis to cDNA molecular clone NL432 of HIV, variousmutant clones of the reverse transcriptase gene known as CDIMI resistantor AZT resistant were prepared. The mutant clones' cDNAs weretransfected to SW480 cells. The produced mutant viruses were infected toMT-4 cells in the same method as described in Experiment 1 in thepresence of the drug. After 4 days, viral growth was assayed usingreverse transcriptase activity as a marker. Fifty % viral growthinhibition (EC₅₀) and 90% viral growth inhibition (EC₉₀) werecalculated. The result is shown in Table 18.

                  TABLE 18                                                        ______________________________________                                                   CDIMI       AZT                                                                 EC.sub.50                                                                             EC.sub.90 EC.sub.50                                                                           EC.sub.90                                Virus        (ng/ml) (ng/ml)   (ng/ml)                                                                             (ng/ml)                                  ______________________________________                                        NL432        0.31    1.1       1.2   5.6                                      (Wild strain)                                                                 Y181C        4.2     18        0.9   3.6                                      F227C        2.4     9.8       0.14  1.1                                      L234I        6.8     14        0.78  3.0                                      V106A + F227L                                                                              117     310       0.58  6.0                                      D67N + K70R  0.31    1.0       2.0   32                                       T215Y        0.17    0.4       5.6   37                                       T215Y + L234I                                                                              0.69    2.7       1.6   6.8                                      ______________________________________                                    

Y181C, F227C, L234I and V106A plus F227L strains imparting CDIMIresistance were sensitive to AZT. Conversely, sensitivity of AZTresistant clones D67N plus K70R and T215Y strains to CDIMI wasequivalent to that of the wild strain. That is, CDIMI and AZT do notshow cross resistance.

T215Y plus L234I strain having both the AZT-resistant mutation T215Y andthe CDIMI-resistant mutation L234I was sensitive to CDIMI and AZT at thesame level as the wild strain's, indicating the revision of theresistant to the sensitive. This in vitro result shows that theemergence of resistant variants to both CDIMI and AZT will be unlikelyin infected patients to whom CDIMI and AZT are administeredsimultaneously.

Formulation 1 Granules

The granules were prepared by mixing uniformly the following eachingredient, fluid-granulating, dried, and filtered.

    ______________________________________                                        CDIMI            20 mg                                                        AZT              25 mg                                                        Starch           15 mg                                                        Lactose          16 mg                                                        Crystalline cellulose                                                                          21 mg                                                        Polyvinyl alcohol                                                                               3 mg                                                        Water            30 mg                                                        Total            130 mg                                                       ______________________________________                                    

Formulation 2 Capsules The capsules were manufactured by mixinguniformly the following each ingredient, and filling the mixture ingelatin capsules.

    ______________________________________                                        CDIMI             35 mg                                                       ddI               55 mg                                                       Lactose           96 mg                                                       Sodium starch glycolate                                                                         13 mg                                                       Magnesium stearate                                                                               1 mg                                                       Total             200 mg                                                      ______________________________________                                    

Formulation 3 Tablets

The tablets of 200 mg were prepared by mixing uniformly the followingingredients other than magnesium stearate and granulated, followed byaddition of magnesium stearate.

    ______________________________________                                        CDIMI             7 mg                                                        ddC               10 mg                                                       Lactose           100 mg                                                      Crystalline cellulose                                                                           75 mg                                                       Talc              5 mg                                                        Carboxymethylcellulose                                                                          2 mg                                                        Magnesium stearate                                                                              1 mg                                                        Total             200 mg                                                      ______________________________________                                    

EFFECT OF INVENTION

As shown obviously in the above experiments, an anti-HIV composition ofthe present invention, as compared with administration of each anti-HIVcompound alone, shows potent synergy in activity, and does not showsynergy in citotoxicity. Accordingly, the composition is an effectivepharmaceutical composition for treating and preventing of AIDS.

What is claimed is:
 1. An anti-HIV composition comprising2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazoleor the pharmaceutically acceptable salt thereof and another one or moreanti-HIV compounds.
 2. The anti-HIV composition as claimed in claim 1,wherein the anti-HIV compounds show synergy in combination with2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazoleor the pharmaceutically acceptable salt thereof, with the proviso thatsaid anti-HIV compounds exclude non-nucleoside reverse transcriptaseinhibitors.
 3. The anti-HIV composition as claimed in claim 1, whereinthe anti-HIV compounds inhibit the emergence of drug resistant HIVviruses in combination with2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazoleor the pharmaceutical acceptable salt thereof.
 4. The anti-HIVcomposition as claimed in claim 1, wherein the anti-HIV compounds are anucleoside reverse transcriptase inhibitor selected from the groupconsisting of AZT, ddI, ddC, d4T and 3TC, a non-nucleoside reversetranscriptase inhibitor selected from the group consisting of3-(5-(3,5-dichlophenvlthio)-4-isopropyl-1-(pyridin-4-ylmethyl-1H-imidazol-2-ylpropan-1-oland2-(5-(3,5-dichlorophenylthio)-1-ethyl-4-isopropyl-1H-imidazol-2-yl)ethanol,and/or an HIV protease inhibitor selected from the group consisting ofsaquinavir, indinavir, ritonavir, nelfinavir and VX-478.
 5. The anti-HIVcomposition as claimed in claim 1 or 2, wherein the anti-HIV compoundsare AZT (azidothymidine) ddI (2',3-dideoxyinosine), ddC(2,3'-dideoxycytidine),3TC(3-thiacytidine),saquinavir, and/or foscarnet.6. A method for treating AIDS which comprises simultaneously orcontinuously administering2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazoleor the pharmaceutically acceptable salt thereof and another one or moreanti-HIV compounds.
 7. The anti-HIV composition as claimed in claim 2,wherein the anti-HIV compounds are AZT (azidothymidine),ddI(2',3-dideoxyinosine),ddC(2,3'-dideoxycytidine),3TC(3'-thiacytidine),saquinavir, and/or foscarnet.
 8. A method for treating AIDS whichcomprises simultaneously or continuously administering2-carbamoyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-yl)methyl-1H-imidazoleor the pharmaceutically acceptable salt thereof and another one or moreanti-HIV compounds.